To study epidermal differentiation and carcinogenesis, cDNA and genomic clones corresponding to the major proteins expressed in mouse epidermis have been isolated and characterized. These include the basal layer keratins K5 and K14, the suprabasal layer keratins Kl and K10, the hyperproliferative keratins K6 and K16, and K13, expressed in malignant tumors, but not in benign tumors or normal epidermis. In addition, cDNA and genomic clones for filaggrin, the protein which organizes keratin filaments into larger bundles, and loricrin, the major precursor protein of the cornified envelope, have been isolated. Monospecific antibodies to the C-terminal amino acid sequences, as well as nucleic acid probes to unique regions of the cDNAs, allow the study of the expression of these markers in normal epidermis, benign and malignant tumors, as well as cells in culture. The coordinate loss of Kl and K10 and the presence of K13 was observed in all malignant tumors. K6 was found in both benign and malignant tumors. Regulation of the expression of these markers is at the transcriptional level. Cells from transgenic mice containing the human Kl gene expressed this gene optimally with the calcium level of the medium adjusted to 0.6 mM; optimum expression of mouse KI was at 0.12 mM calcium in the same cells. The induction of mouse Kl was suppressed by retinoic acid, but human Kl was unaffected. Thus, regulatory elements of the human KI gene that determine response to calcium and retinoic acid differ from the regulatory sequences for mouse KI. Retinoic acid, reported to be both an anticarcinogen and a tumor promoter in animals, is widely used as an anti- wrinkle cosmetic. In samples from retinoic acid-treated patients, the hyperproliferative keratin K6 was expressed in 5 of 10 samples, while K13, a carcinoma marker, was seen in 3 of 10 samples. The changes did not correlate with cosmetic improvement.